Mesotrypsin, encoded by the PRSS3 gene, is a distinctive trypsin isoform renowned for its exceptional resistance to traditional trypsin inhibitors and unique substrate specificity. Within the skin epidermis, this protein primarily expresses in the upper layers of the stratified epidermis and plays a crucial role in processing pro-filaggrin (Pro-FLG). Although prior studies have partially elucidated its functions using primary cultured keratinocytes, challenges persist due to these cells\' differentiation-activated cell death program. In the present study, HaCaT keratinocytes, characterized by minimal endogenous mesotrypsin expression and sustained proliferation in differentiated states, were utilized to further scrutinize the function of mesotrypsin. Despite the ready degradation of the intact form of active mesotrypsin in these cells, fusion with Venus, flanked by a peptide linker, enables evasion from the protein elimination machinery, thus facilitating activation of the Pro-FLG processing system. Inducing Venus-mesotrypsin expression in the cells resulted in a flattened phenotype and reduced proliferative capacity. Moreover, these cells displayed altered F-actin assembly, enhanced E-cadherin adhesive activity, and facilitated tight junction formation without overtly influencing epidermal differentiation. These findings underscore mesotrypsin\'s potentially pivotal role in shaping the characteristic cellular morphology of upper epidermal layers.

Background: Fractures through the physis account for 18-30% of all paediatric fractures, leading to growth arrest in up to 5.5% of cases. We have limited knowledge to predict which physeal fractures result in growth arrest and subsequent deformity or limb length discrepancy. The purpose of this study is to identify factors associated with physeal growth arrest to improve patient outcomes. Methods: This prospective cohort study was designed to develop a clinical prediction model for growth arrest after physeal injury. Patients ≤ 18 years old presenting within four weeks of injury were enrolled if they had open physes and sustained a physeal fracture of the humerus, radius, ulna, femur, tibia or fibula. Patients with prior history of same-site fracture or a condition known to alter bone growth or healing were excluded. Demographic data, potential prognostic indicators, and radiographic data were collected at baseline, during healing, and at one- and two-years post-injury. Results: A total of 332 patients had at least six months of follow-up or a diagnosis of growth arrest within six months of injury. In a comparison analysis, patients who developed growth arrest were more likely to be older (12.8 years vs. 9.4 years) and injured on the right side (53.0% vs. 45.7%). Initial displacement and angulation rates were higher in the growth arrest group (59.0% vs. 47.8% and 47.0% vs. 38.8%, respectively), but the amount of angulation was similar (27.0° vs. 28.4°). Rates of growth arrest were highest in distal femoral fractures (86%). Conclusions: The incidence of growth arrest in this patient population appears higher than the past literature reports at 30.1%. However, there may be variances in diagnostic criteria for growth arrest, and the true incidence may be lower. A number of patients were approaching skeletal maturity, and any growth arrest is likely to have less clinical significance in these cases. Further prospective long-term follow-up is required to determine risk factors, incidence, and true clinical impact of growth arrest when it does occur.

BACKGROUND: Atrophic autoimmune thyroiditis (AAT) is a rare phenotype of autoimmune thyroiditis (AT) in pediatric age. AAT occurs without thyroid enlargement leading to a delay in its diagnosis. Growth impairment is infrequent in autoimmune thyroiditis, if timely diagnosed. Prolonged severe hypothyroidism is a rare cause of pituitary hyperplasia (PH) in childhood. Loss of thyroxine negative feedback causes a TRH-dependent hyperplasia of pituitary thyrotroph cells resulting in adenohypophysis enlargement. A transdifferentiation of pituitary somatotroph cells into thyrotroph cells could explain growth failure in those patients.
METHODS: Twelve patients were retrospectively evaluated at five Italian and Polish Centres of Pediatric Endocrinology for height growth impairment. In all Centres, patients underwent routine clinical, biochemical and radiological evaluations.
RESULTS: At the time of first assessment, the 75% of patients presented height growth arrest, while the remaining ones showed growth impairment. The study of thyroid function documented a condition of hypothyroidism, due to AT, in the entire cohort, although all patients had no thyroid enlargement. Thyroid ultrasound showed frankly atrophic or normal gland without goiter. Cerebral MRI documented symmetrical enlargement of the adenohypophysis in all patients and a homogeneous enhancement of the gland after the administration of Gadolinium-DPTA. Replacement therapy with levothyroxine was started and patients underwent close follow-up every 3 months. During the 12 months of follow-up, an improvement in terms of height growth has been observed in 88% of patients who continued the follow-up. Laboratory findings showed normalization of thyroid function and the control brain MRI documented complete regression of PH to a volume within the normal range for age and sex.
CONCLUSIONS: This is the largest pediatric cohort with severe autoimmune primary hypothyroidism without goiter, but with pituitary hyperplasia in which significant growth impairment was the most evident presenting sign. AAT phenotype might be correlated with this specific clinical presentation. In youths with growth impairment, hypothyroidism should always be excluded even in the absence of clear clinical signs of dysthyroidism.

[This corrects the article DOI: 10.3389/fphar.2019.01287.].

BACKGROUND: Simple bone cysts (SBC) are benign tumor-like bone lesions typically identified in children. While SBC may lead to growth disturbances or growth arrest, such cases are uncommon. The mechanisms behind these observations remain unclear. Additionally, research on the etiology of SBC remains inconclusive, and there has been no consensus on the appropriate timing and methodology for treatment.
METHODS: Here, we present our experience in the successful surgical management of a 10-year-old girl with SBC, who presented with a pathological fracture complicated by malunion of the displaced fracture, varus deformity, and limb length discrepancy. We hypothesized two possible etiologies for the patient\'s growth arrest and subsequent humerus varus deformity: (1) Direct disruption of the physis by fluid from the cyst itself; and (2) damage to the epiphysis due to repetitive pathological fractures associated with SBC. In addressing this case, surgical intervention was undertaken to correct the proximal humerus varus deformity. This approach offered the advantages of simultaneously correcting angular abnormalities, achieving mild limb lengthening, providing definitive SBC treatment, and reducing the overall treatment duration.
CONCLUSIONS: As per current literature, acute correction of acute angular deformity in proximal humeral SBC is not well comprehended. However, in this specific case, acute correction was considered an optimal solution.

The peptide mimetic, NC114, is a promising anticancer compound that specifically kills colorectal cancer cells without affecting normal colon epithelial cells. In our previous study, we observed that NC114 inhibited the Wnt/β-catenin pathway, with significant downregulation of both Ser 675-phosphorylated β-catenin and its target genes, cyclin D1 and survivin. However, the molecular mechanism responsible for its cytotoxic effect has not yet been fully characterized. In the present study, we demonstrated that NC114 prevented cell cycle progression from S to G2/M phase by downregulating cell cycle-related gene expression, and also induced growth arrest in SW480 and HCT-116 colorectal cancer cells. A novel covariation network analysis combined with transcriptome analysis revealed a series of signaling cascades affected by NC114 treatment, and identified protein kinase C-δ (PKCδ) and forkhead box protein M1 (FOXM1) as important regulatory factors for NC114-induced growth arrest. NC114 treatment inhibits the activation of PKCδ and its kinase activity, which suppresses MEK/ERK signaling. Attenuated MEK/ERK signaling then results in a reduction in FOXM1 phosphorylation and subsequent nuclear translocation of FOXM1 and β-catenin. Consequently, formation of a T-cell factor-4 (TCF4)/β-catenin transcription complex in the nucleus is inhibited and transcription of its target genes, such as cell cycle-related genes, is downregulated. The efficacy of NC114 on tumor growth was confirmed in a xenograft model. Collectively, elucidation of the mechanism by which NC114 induces growth arrest in colorectal cancer cells should provide a novel therapeutic strategy for colorectal cancer treatment.

UNASSIGNED: Following trauma, premature growth arrest is a common outcome when the injury affects the pediatric growth plate. Dactylitis describes global inflammation affecting one or more digits in the hand or foot. It occurs in various seronegative arthropathies and septic arthritis. Physeal fusion following dactylitis is uncommon and is not described in the current literature.
UNASSIGNED: We report the case of a 12-year-old boy, whose minor non-penetrating injury resulted in circumferential edema of his left third upper limb digit, typical of dactylitis. No evidence of infection was found during clinical examination or blood work. Significant stiffness of the digit remained over the course of a few months with spontaneous resolution following functional hand therapy. The child presented to pediatric orthopedics with cessation of longitudinal growth. Evidence of premature physeal fusion of the involved phalanges was confirmed on radiographs.
UNASSIGNED: Growth arrest following dactylitis has not previously been reported. Clinicians managing this condition should be aware of this rare complication. We recommend that inflammation is treated promptly, and patients are monitored clinically and radiologically to address any potential functional deficit.

UNASSIGNED: Level V.

Quiescence, the temporary and reversible arrest of cell growth, is a fundamental biological process. However, the lack of standardization in terms of reporting the experimental details of quiescent cells and populations can cause confusion and hinder knowledge transfer. We employ the systematic review methodology to comprehensively analyze the diversity of approaches used to study the quiescent state, focusing on all published research addressing the budding yeast Saccharomyces cerevisiae. We group research articles into those that consider all cells comprising the stationary-phase (SP) population as quiescent and those that recognize heterogeneity within the SP by distinguishing phenotypically distinct subpopulations. Furthermore, we investigate the chronological age of the quiescent populations under study and the methods used to induce the quiescent state, such as gradual starvation or abrupt environmental change. We also assess whether the strains used in research are prototrophic or auxotrophic. By combining the above features, we identify 48 possible experimental setups that can be used to study quiescence, which can be misleading when drawing general conclusions. We therefore summarize our review by proposing guidelines and recommendations pertaining to the information included in research articles. We believe that more rigorous reporting on the features of quiescent populations will facilitate knowledge transfer within and between disciplines, thereby stimulating valuable scientific discussion.

c-di-GMP primarily controls motile to sessile transitions in bacteria. Diguanylate cyclases (DGCs) catalyze the synthesis of c-di-GMP from two GTP molecules. Typically, bacteria encode multiple DGCs that are activated by specific environmental signals. Their catalytic activity is modulated by c-di-GMP binding to autoinhibitory sites (I-sites). YfiN is a conserved inner membrane DGC that lacks these sites. Instead, YfiN activity is directly repressed by periplasmic YfiR, which is inactivated by redox stress. In Escherichia coli, an additional envelope stress causes YfiN to relocate to the mid-cell to inhibit cell division by interacting with the division machinery. Here, we report a third activity for YfiN in E. coli, where cell growth is inhibited without YfiN relocating to the division site. This action of YfiN is only observed when the bacteria are cultured on gluconeogenic carbon sources, and is dependent on absence of the autoinhibitory sites. Restoration of I-site function relieves the growth-arrest phenotype, and disabling this function in a heterologous DGC causes acquisition of this phenotype. Arrested cells are tolerant to a wide range of antibiotics. We show that the likely cause of growth arrest is depletion of cellular GTP from run-away synthesis of c-di-GMP, explaining the dependence of growth arrest on gluconeogenic carbon sources that exhaust more GTP during production of glucose. This is the first report of c-di-GMP-mediated growth arrest by altering metabolic flow. IMPORTANCE The c-di-GMP signaling network in bacteria not only controls a variety of cellular processes such as motility, biofilms, cell development, and virulence, but does so by a dizzying array of mechanisms. The DGC YfiN singularly represents the versatility of this network in that it not only inhibits motility and promotes biofilms, but also arrests growth in Escherichia coli by relocating to the mid-cell and blocking cell division. The work described here reveals that YfiN arrests growth by yet another mechanism in E. coli, changing metabolic flow. This function of YfiN, or of DGCs without autoinhibitory I-sites, may contribute to antibiotic tolerant persisters in relevant niches such as the gut where gluconeogenic sugars are found.